This invention provides O-xcex1-acyloxyalkyl ethers of 4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, as well as pharmaceutical compositions and uses thereof.
Various patents and literature references describe the biological activities of venlafaxine, and its salts and analogs. Venlafaxine hydrochloride tablets are marketed by Wyeth-Ayerst Laboratories as EFFEXOR.
The absolute configuration of the (+) enantiomer of venlafaxine was established as S by a single crystal X-ray analysis of the hydrobromide salt and the anomalous dispersion technique (Yardley et al., J. Med. Chem., 1990, 33, 2899).
(R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol and its metabolites 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol and 1-[1-(4-methoxyphenyl)-2-(methylamino)ethyl]cyclohexanol are disclosed and claimed in U.S. Pat. No. 4,535,186 (Husbands et al.). U.S. Pat. No. 5,530,013 (Husbands et al.) claims the use of venlafaxine in the inducement of cognition enhancement. U.S. Pat. No. 5,506,270 (Upton et al.) claims venlafaxine""s use in methods of treating hypothalamic amenorrhea in non-depressed women.
U.S. Pat. No. 5,788,986 (Dodman) and U.S. Pat. No. 5,554,383 (Dodman) teaches and claims the use of serotonin reuptake inhibitors in modifying the behavior of dogs.
This invention provides pharmaceutically active O-xcex1-acyloxyalkyl ethers of the venlafaxine metabolite 4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol (xe2x80x9cO-Desmethyl venlafaxinexe2x80x9d or xe2x80x9cODVxe2x80x9d) having the structural formula I 
wherein
the configuration at the steriogenic center (*) may be R, S, or RS (the racemate);
R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or the moiety: 
R2 is selected from H, or C1-C6 alkyl; or,
R1 and R2 may be concatenated such that 
xe2x80x83form a moiety having formula (b): 
R3 is selected from H or C1-C6 alkyl; and
R4 and R5 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 thioalkoxy, xe2x80x94CN, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCF3, halogen, xe2x80x94NH2, xe2x80x94NO2, or xe2x80x94N(CH3)2, or pharmaceutically acceptable salts or hydrates thereof.
In some preferred embodiments of the present invention R1 is t-butyl, methoxy, or isobenzofuranone.
In other preferred embodiments of the invention R2 is C1-C3 alkyl and in still more preferred embodiments of the invention R2 is methyl. Specific examples of compounds of Formula I include:
{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methyl pivalate;
1-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}ethyl propionate; and
3-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}-2-benzofuran-1(3H)-one.
Particularly, this invention provides compounds and/or compositions of both the O-xcex1-acyloxyalkyl R-ether of Formula I and the O-xcex1-acyloxyalkyl S-ether of Formula I, both being substantially free of the other. In addition, the invention provides the O-xcex1-acyloxyalkyl RS-ether of 4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]-phenol of Formula I.
Substantially free, as used herein means the compound or composition is made up of significantly greater proportion of the desired isomer than of the optical antipode. In a preferred embodiment of the invention, xe2x80x9csubstantially freexe2x80x9d means that the compound or composition is made up of at least about 90% of the desired isomer and about 10% or less of the optical antipode. In still more preferred embodiments of the present invention, the compound or composition is made up of at least about 95% of the desired isomer and about 5% or less of the optical antipode. In yet further embodiments of the present invention the compound or composition is made up of at least about 99% of the desired isomer and about 1% or less of the optical antipode. Preferably the characterized or separated enantiomer will exhibit physical properties of a fully characterized compound, i.e. a uniform melting point and a uniform rotation of plane-polarized light in a polarimeter. Most preferably, the enantiomers will be recrystallized to analytical purity.
C1-C6 alkyl as used herein, such as in the definition of R1, includes straight, branched chain alkyl groups within the specified range of carbon atoms.
Halogen, as used herein refers to chlorine, bromine, iodine and fluorine.
Pharmaceutically acceptable salts refer to salts prepared from pharmaceutically acceptable acids, including inorganic acids and organic acids, such as, but not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, mitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like.
Compounds of the invention are readily prepared by methods known in the art, for instance, as described by Bodor, et al., J. Org. Chem.(48) 5280-5284 (1983).
The appropriate R-, S-, or (R/S)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol is reacted with the appropriate O-xcex1-acyloxyalkyl halide (examples: pivaloyloxymethyl chloride, 3-bromophthalide, iodomethyl pivalate) (Scheme Ia) or (acyloxy)benzyl xcex1-halide (Scheme Ib) in an inert solvent (acetonitrile, tetrahydrofuran, dimethylformamide) in the presence of an alkali metal carbonate (sodium or potassium carbonate) or transition metal carbonate (silver carbonate) in accordance with Schemes Ia and Ib. 
wherein R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or the moiety: 
R2 is selected from H, or C1-C6 alkyl;
or R2 and R3 are concatenated to form a moiety having formula (b);
R3 is selected from H or C1-C6 alkyl; and
R4 and R5 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 thioalkoxy, xe2x80x94CN, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCF3, halogen, xe2x80x94NH2, xe2x80x94NO2, or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms.
In some preferred embodiments of the invention increased yield may be obtained by reacting the appropriate R-, S-, or (RIS)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol with the appropriate O-xcex1-acyloxyalkyliodide in an inert solvent (acetonitrile, tetrahydrofuran, dimethylformamide) in the presence of alkali metal carbonate such as potassium carbonate, or transition metal carbonate such as silver carbonate. Most preferred is the use of O-xcex1-acyloxyalkyliodide in the presence of silver carbonate at low temperatures in the range of approximately 0-5xc2x0 C.
In a minor modification, compounds of formula I wherein R1 and R2 are concatenated to form 
and one or both of R4 and R5 are NH2, can be obtained by catalytic reductions, such as with palladium catalysts, from corresponding analogs wherein R4 or R5 are NO2.
Racemic 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol can be produced as described in Example 26 of U.S. Pat. No. 4,535,186 (Husbands et al.), which is incorporated herein by reference. It will be understood that the enantiomers may be separated from each other by standard resolution techniques known in the art.
Alternatively, these R and S enantiomers may be obtained by O-demethylation of the separated enantiomers of venlafaxine using either boron tribromide or ethane thiol anion.
O-xcex1-acyloxyalkyl ethers of Formula I and their pharmaceutically useful salts and hydrates are useful for the biological and pharmacological activities for which venlafaxine and its salts are known in the art. These O-xcex1-acyloxyalkyl ethers may be used in treating or inhibiting central nervous system disorders, including depression, (including but not limited to major depressive disorder, biopolar disorder, and dysthymia), fibromyalgia, anxiety, panic disorder, agoraphobia, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder (including trichotillomania), social anxiety disorder, generalized anxiety disorder, autism, schizophrenia, obesity, anorexia nervosa, bulimia nervosa, Gilles de la Tourette Syndrome, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction (including premature ejaculation), borderline personality disorder, chronic fatigue syndrome, urinary incontinence, pain (including but not limited to migraine, chronic back pain, phantom limb pain, central pain, neuropathic pain such as diabetic neuropathy and postherpetic neuropathy), Raynaud""s syndrome, and others. These compounds are also useful in the inducement of cognition enhancement and in regimens for cessation of smoking or other tobacco uses.
This invention also includes methods of treating, preventing, inhibiting or alleviating each of the maladies listed above in a mammal, preferably in a human, the methods comprising providing a pharmaceutically effective amount of a compound of this invention to the mammal in need thereof.
xe2x80x9cProvidingxe2x80x9d as used herein with respect to providing a compound or substance covered by the invention, means either directly administering such a compound or substance, or administering a prodrug, derivative or analog which forms an equivalent amount of the compound or substance within the body.
A pharmaceutically effective dose will include those doses which provide the relief or prevention sought for the malady in question. The compounds of this invention may be provided in the dosages and pharmaceutical formulations known in the art as useful for venlafaxine hydrochloride (such as those doses known for the venlafaxine hydrochloride products marketed by Wyeth-Ayerst Laboratories under the Effexor(copyright) trademark). It will be understood that the initial dose, increases therefrom and final daily administration will be determined by a medical professional considering the needs and conditions for each recipient. For instance, a daily dose for an adult human may be from about 75 mg to about 450 mg per day, preferably between about 75 and about 225 mg per day. An initial dose of 75 mg per day may be administered, with increases as determined by a medical professional.
This invention also includes pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of this invention and one or more pharmaceutically acceptable carriers or excipients. A preferred method of administration includes the use of the present compounds in extended release formulations of the type described in published PCT application WO 99/22724 (Sherman et al.)., which is incorporated herein by reference.